Process of production of 4-substituted-3-halogeno-1,4-benzoxazepine derivative and salts thereof

ABSTRACT

A process for producing 4-substituted-3-halogeno-1,4-benzoxazepin derivative or the salt thereof comprising: deprotonizing a benzoxazepine derivative having the formula (II): ##STR1##  with a base; and then, reacting the deprotonized product with a phosphate halide to produce an intermediate having the formula (IV): ##STR2##  and then, reacting the resultant intermediate (IV) with a reagent selected from (i) a complex of a phosphine with chlorine or bromine, (ii) a phosphine and a chlorine gas or liquid bromine, (iii) a phosphine and tetrachloromethane or tetrabromomethane, or (iv) a halogenated phosphite ester to produce a 4-substituted-3-halogeno-1,4-benzoxazepine derivative having the formula (I) ##STR3##  wherein X indicates a chlorine atom or a bromine atom, or its salt.

This application is a 371 of PCT/JP98/03153 filed Jul. 14, 1998.

TECHNICAL FIELD

The present invention relates to process for the production of a4-substituted-3-halogeno-1,4-benzoxazepine derivative and the saltsthereof, which are useful as a pharmaceutical or as a starting materialor intermediate for the synthesis thereof.

BACKGROUND ART

A 4-substituted-3-halogeno-1,4-benzoxazepine derivative is an importantcompound usable as a pharmaceutical for psychoneurotic disorders such asanxiety neurosis, phobias, obsessive-compulsive disorders,schizophrenia, post-cardiac trauma stress disorders, depressiondisorders, and psychosomatic disorders, disorders such as eatingdisorders, menopausal disorders, infantile autism and also emesis ordisorders involving the cerebral circulatory system accompanyingcerebral infarction and cerebral hemorrhaging or as a synthetic startingmaterial or an intermediate of pharmaceuticals etc. However, industrialprocesses for production thereof which have been fully satisfactory interms of the operability and yield, are not known in the art.

A process for synthesis of a 4-substituted-3-halogeno-1,4-benzoxazepinederivative is disclosed in, for example, International PublicationWO96-24594. That is, this process comprises reacting a benzoxazepinederivative with an acid chloride such as phosphorus oxychloride (POCl₃),thionyl chloride (SOCl₂), while adding acid such as hydrochloric acid ora base such as N,N-diethylaniline, if necessary. However, in thisprocess, since a large amount of acid chloride is used, there is theaccompanying risk of the generation of hydrochloric acid gas and asudden rise in temperature and the generation of bumping, etc. in theneutralization reaction for treatment and decomposition of the excessiveacid chloride and, therefore, there was the industrial difficulty.Further, in terms of the yield as well, the yield was 30 to 60%--whichcannot be necessarily said to be good. Further, there was the problemthat the benzoxazepine derivative starting material would remain in thereaction solution in considerable amounts and it was difficult toseparate the starting material compound and the target compound.

In this way, no process has been known which has been fully satisfactoryfor the industrial production of a4-substituted-3-halogeno-1,4-benzoxazepine derivative. Therefore, a newprocess for production of a 4-substituted-3-halogeno-1,4-benzoxazepinederivative is necessary to be developed.

SUMMARY OF THE INVENTION

Accordingly, an object of the present invention is to provide a newprocess for production of a 4-substituted-3-halogeno-1,4-benzoxazepinederivative and the salts thereof which are easy to operate and which areindustrially satisfactory and which are good yield.

Another object of the present invention is to provide an industriallysatisfactory process for production of a benzoxazepine derivative andthe salts thereof using the above process.

In accordance with the present invention, there is provided a4-substituted-3-halogeno-1,4-benzoxazepine derivative having the formula(I): ##STR4##

wherein, R indicates a hydrogen atom, halogen atom, C₁ to C₄ lower alkylgroup, C₁ to C₄ lower alkoxy group, or hydroxy group, preferably ahydrogen atom or halogen atom, and A indicates a C₂ to C₅ halogenoalkylgroup or a group having the formula (III): ##STR5##

wherein, n is an integer of 2 to 5, the dotted line indicates thepresence or absence of a bond, W indicates a carbon atom, methine,methylene, or nitrogen atom, where when W is a nitrogen atom, Z bondswith W and the dotted line indicates the absence of a bond, and Zindicates an aromatic hydrocarbon group which may be substituted, or aheterocyclic group which may be substituted, preferably a C₂ -C₅halogenoalkyl group or a group having the formula (XXVI) or (XXVII):##STR6## wherein n is an integer of 2 to 5, Ar is a phenyl group,2-pyridyl group or 2-pyrimidinyl group, X indicates a chlorine atom orbromine atom, preferably a chlorine atom, can be produced bydeprotonizing, using a base, a benzoxazepine derivative having theformula (II): ##STR7##

wherein, R and A are the same as defined above, then reacting thedeprotonized product with a phosphate halide to produce an intermediatehaving the formula (IV): ##STR8## wherein, R and A are as defined above,and R₁ and R₂, independently, indicate, a C₁ to C₂ lower alkyl group orphenyl group or R₁ and R₂ together indicate an ethylene group (--CH₂ CH₂--), then

reacting this intermediate (IV) with a reagent selected from (i) acomplex of a tri(C₁ to C₄) alkylphosphine, triarylphosphine, orphenyldi(C₁ to C₄) alkylphosphine with chlorine or bromine, (ii) atri(C₁ to C₄) alkylphosphine, triarylphosphine, or phenyldi(C₁ to C₄)alkylphosphine and chlorine gas or liquid bromine, (iii) tri(C₁ to C₄)alkylphosphine, triarylphosphine, or phenyldi(C₁ to C₄) alkylphosphineand tetrachloromethane or tetrabromomethane, or (iv) a halogenatedphosphite ester to produce the4-substituted-3-halogeno-1,4-benzoxazepine derivative (I).

BEST MODE FOR CARRYING OUT THE INVENTION

The present inventors engaged in intensive research with the aim ofdevelopment of an industrial process of production of a4-substituted-3-halogeno-1,4-benzoxazepine derivative in view of theabove situation and, as a result, found that, by using a startingmaterial having the above formula (II) to derive a phosphate esterhaving the formula (IV) and then react this intermediate (IV) with areagent selected from (i) a complex of a tri(C₁ to C₄) alkylphosphine(for example, Me₃ P, Et₃ P, Pr₃ P, BU₃ P), triarylphosphine (preferably,triphenylphosphine), or phenyldi(C₁ to C₄) alkylphosphine (preferably,PhPMe₂, PhPEt₂) with chlorine or bromine, (ii) a tri(C₁ to C₄)alkylphosphine, triarylphosphine, or phenyldi(C₁ to C₄) alkylphosphineand chlorine gas or liquid bromine, (iii) a tri(C₁ to C₄)alkylphosphine, triarylphosphine, or phenyldi(C₁ to C₄) alkylphosphineand tetrachloromethane or tetrabromomethane, or (iv) a halogenated(preferably, chlorinated or brominated) phosphite ester, it was possibleto obtain a 4-substituted-3-halogeno-1,4-benzoxazepine derivative easilyand with a good yield.

The starting material, that is, the compound having the above formula(II), can be prepared by the process disclosed in InternationalPublication WO96-24594. The compound having the above formula (IV) canbe obtained by deprotonizing the compound having the above formula (II)with a base such as potassium tert-butoxide, potassiumbis(trimethylsilyl)amide, sodium bis(trimethylsilyl) amide, sodiumhydride, triethylamine, lithium bis(trimethylsilyl)amine or sodiumamide, then treating the resultant product with a phosphate chloridecompound such as diethyl chlorophosphate, diphenyl chlorophosphate, or2-chloro-1,3,2-dioxaphospholane-2-oxide.

The desired 4-substituted-3-halogeno-1,4-benzoxazepine derivative havingthe formula (I) can be produced by the method of combining the compoundthus obtained having the above formula (IV) with a commerciallyavailable triphenylphosphine-chlorine complex,triphenylphosphine-bromine complex, or triphenylphosphine andtetrahalogenomethane (for example, CCl₄).

Due to the development of the process according to the presentinvention, it is possible to avoid the occurrence of sudden rises intemperature or bumping accompanying the neutralization and decompositionof the reagents and improve the separation and yield compared with theconventional process disclosed in the International PublicationWO96-24594. Further, the problem of separation of the starting materialcompound and the target compound is also solved and industrialproduction becomes easier. A useful new process of production for the4-substituted-3-halogeno-1,4-benzoxazepine derivative having the aboveformula (I) has therefore been developed. Further, by using thisprocess, it is also possible to obtain industrially useful benzoxazepinederivatives and their salts in accordance with the process described inthe International Publication WO96-24594.

I) Process of Production of Intermediate having Above Formula (IV)

The phosphate halide usable in the process of production of theintermediate having the above formula (IV) is preferably dimethylchlorophosphate, diethyl chlorophosphate, diphenyl chlorophosphate,2-chloro-1,3,2-dioxaphospholane-2-oxide, more preferably diethylchlorophosphate, diphenyl chlorophbsphate, or2-chloro-1,3,2-dioxaphospholane-2-oxide, most preferably diethylchlorophosphate. These phosphate halides are used in amounts ofpreferably 1 to 3 equivalents, more preferably 1 to 1.2 equivalents, ofthe compound having the above formula (II).

The base which may be used in the reaction is preferably sodium hydride,sodium bis(trimethylsilyl) amide, potassium bis(trimethylsilyl)amide,lithium bis(trimethylsilyl)amide, sodium amide, or lithiumdiisopropylamide, more particularly sodium bis(trimethylsilyl)amide,potassium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, orlithium diisopropylamide, most preferably sodiumbis(trimethylsilyl)amide or potassium bis(trimethylsilyl)amide. Thesebases may be used in amounts of preferably 1 to 2 equivalents, morepreferably 1 to 1.2 equivalents, of the compound having the aboveformula (II).

The reaction temperature of the reaction is not particularly limited,but preferably it is -100° C. to room temperature, more preferably -78°C. to 0° C. Further, the reaction is performed in the presence of anorganic solvent. As the organic solvent, preferably tetrahydrofuran,diethyl ether, or ethylene glycol diethyl ether, more preferablytetrahydrofuran or diethyl ether, may be mentioned.

II) Process for Production of Compound having Above Formula (I) FromIntermediate having Formula (IV)

The reaction product used for the process of production of the4-substituted-3-chloro-1,4-benzoxazepine derivative where X=Cl in thecompounds having the above formula (I) is preferably atriphenylphosphine-chlorine complex, chlorine in the copresence oftriphenylphosphine, carbon tetrachloride in the copresence oftriphenylphosphine, diethyl chlorophosphite, or phosphorus oxychloride,more preferably a triphenylphosphine-chlorine complex, chlorine in thecopresence of triphenylphosphine, carbon tetrachloride in the copresenceof triphenylphosphine, or diethyl chorophosphite, most preferably atriphenylphosphine-chlorine complex.

The reaction product used for the process of production of the4-substituted-3-bromo-1,4-benzoxazepine derivative where X=Br in thecompounds having the above formula (I) is preferably atriphenylphosphine-bromine complex, bromine in the copresence oftriphenylphosphine, or carbon tetrabromide in the copresence oftriphenylphosphine, more preferably a triphenylphosphine-bromine complexor carbon tetrabromide in the copresence of triphenylphosphine, mostpreferably a triphenylphosphine-bromine complex.

These reagents may be used in amounts of preferably 1 to 10 equivalents,more preferably 1 to 5 equivalents, most preferably 1 to 2 equivalentsof the compound having the above formula (IV).

The reaction temperature of the reaction is not particularly limited,but preferably it is 0° C. to 80° C., more preferably room temperatureto 80° C. Further, the reaction is normally performed in the presence ofan organic solvent. As the organic solvent used in the reaction,preferably tetrahydrofuran, diethyl ether, ethylene glycol diethylether, acetonitrile, methylene chloride, 1,2-dichloroethane, hexane, ordimethyl formamide, more preferably tetrahydrofuran, diethyl ether,acetonitrile, methylene chloride, or 1,2-dichloroethane may bementioned.

III) Process of Production of Benzoxazepine Derivative (Ib) With A ofGroup having Formula (III) in Compounds having Formula (I) From Compound(Ib) With A of Halogenoalkyl in Compounds of Formula (I)

The compound having the formula (Ib) may be synthesized by condensationby an ordinary method of the intermediate compound having the formula(Ia) ##STR9##

wherein, A' indicates a halogenoalkyl, and R and X are as the same asdefined above ##STR10##

wherein, R and X are as defined above, n is an integer of 2 to 5, thedotted line indicates the presence or absence of a bond, W indicates C,CH, or CH₂ or N, where, when W is a nitrogen atom, Z bonds with W andthe dotted line indicates the absence of a bond, and Z indicates asubstitutable aromatic hydrocarbon cyclic group or substitutableheterocyclic group with an intermediate compound of the formula (IX):##STR11##

wherein W and Z are as defined above.

Further, in the intermediate compound having the formula (Ia) providedin accordance with the present invention, as preferable examples of thehalogenoalkyl group having A' in the formula, chloropentyl, bromopentyl,iodopentyl, chlorobutyl, bromobutyl, iodobutyl, chloropropyl,bromopropyl, and iodopropyl may be mentioned. In particular,chlorobutyl, bromobutyl, and iodobutyl are preferable. In the formula,as preferable examples of the group X, a chlorine atom and a bromineatom may be mentioned. In particular, a chlorine atom is preferred. Aspreferable examples of the group R, a hydrogen atom, halogen atom, C₁ toC₂ lower alkyl group, C₁ to C₂ lower alkoxy group, and hydroxy group maybe mentioned. In particular, a hydrogen atom, fluorine atom, chlorineatom, methyl group, and methoxy group are preferred.

IV) Process of Production of Benzoxazepine Derivative having Formula (V)##STR12##

wherein n, R, X, and Z are as defined above.

The compound having the formula (V) may be produced by condensation ofthe benzoxazepine derivative having the formula (Ia) and the piperadinederivative having the formula (X): ##STR13##

wherein Z is as defined above using, if necessary, a base such astriethylamine or a catalyst such as sodium iodide or other catalyst.

V) Process for Production of a Benzoxazepine Derivative having theFormula (VI)

The compound having the formula (VI) ##STR14##

wherein n, X, and R are as defined above, the dotted line indicates thepresence or absence of a bond, and Z' indicates a heterocyclic groupwhich may be substituted

can be synthesized by condensation with an ordinary method of thebenzoxazepine derivative having the formula (Ia) and the intermediatecompound having the formula (XI): ##STR15##

wherein, Z' is as defined above.

VI) Process of Production of Benzoxazepine Derivative having Formula(VIII) ##STR16##

wherein, R, n, X, and Z' are as defined above, and X₁ indicates ahalogen atom.

These are useful as synthetic intermediates of the benzoxazepinederivatives and their salts having formulas (Ib) or (VI).

The benzoxazepine derivative having formula (VIII) may be produced, forexample, in the following way:

The benzoxazepine derivative having formula (Ia) may be condensed withthe pyridine derivative having the formula (VII): ##STR17##

wherein, Z' is as defined above by an ordinary method.

Specific embodiments of the compounds having the formulas (Ib), (V), and(VI) provided in accordance with the present invention will be explainedin detail below using the Examples, but of course the present inventionis not limited to these Examples.

In the compounds having the formulas (Ib) and (V) and (VI), aspreferable examples of the integers n in the formulas, 3 to 5 may bementioned. In particular, 4 is preferred. As preferable examples of thegroup X in the formulas (Ib) and (V) and (VI), a chlorine atom andbromine atom may be mentioned. In particular, a chlorine atom ispreferable. As preferable examples of the group R, a hydrogen atom,halogen atom, C₁ to C₂ lower alkyl group, C₁ to C₂ lower alkoxy group,and hydroxy group may be mentioned. In particular, a hydrogen atom,fluorine atom, chlorine atom, methyl group, and methoxy group are morepreferred. Further, as preferable examples of the group Z, a monocyclicor polycyclic aromatic group or heterocyclic group, selected from aphenyl group, naphthyl group, pyridyl group, pyrimidinyl group,pyradinyl group, pyridazinyl group, quinolyl group, isoquinolyl group,quinoxalinyl group, quinazolinyl group, 2-thiazolyl group, 2-oxazolylgroup, 2-benzothiazolyl group, 2-benzoxazolyl group, 3-isothiazolylgroup, 2-thienyl group, and 3-thienyl group substitutable with hydrogen,C₁ to C₄ lower alkyl group, C₁ to C₄ lower alkoxy group, hydroxy group,amino group, and/or halogen atom, may be mentioned. In particular, agroup selected from phenyl group, naphthyl group, pyridyl group,pyrimidinyl group, quinoxalinyl group, quinolyl group, isoquinolylgroup, and quinazolinyl group, substitutable with hydrogen, a methylgroup, methoxy group, hydroxy group, amino group, chlorine atom, and/orfluorine atom is preferred. Further, as preferable examples of the groupZ', hydrogen, a monocyclic or polycyclic heterocyclic group,substitutable with a C₁ to C₄ lower alkyl group, C₁ to C₄ lower alkoxygroup, hydroxy group, amino group, and/or a halogen atom selected from apyridyl group, pyrimidinyl group, pyradinyl group, pyridazinyl group,quinolyl group, isoquinolyl group, quinoxalinyl group, quinazolinylgroup, 2-thiazolyl group, 2-oxazolyl group, 2-benzothiazolyl group,2-benzoxazolyl group, 3-isothiazolyl group, 2-thienyl group, and3-thienyl group may be mentioned. In particular, a group selected frompyridyl group, pyrimidinyl group, quinoxalinyl group, quinolyl group,isoquinolyl group, and quinazolinyl group, substitutable with hydrogen,a methyl group, methoxy group, hydroxy group, amino group, chlorineatom, and/or fluorine atom is preferred.

The intermediate usable for the production of the compound having theformula (VI), that is, the compound having the formula (XI), may besynthesized as follows. That is, of the compounds (XI), the pyrimidinederivative having the formula (XII): ##STR18##

wherein, R³ and R⁴ independently indicate a hydrogen atom, halogen atom,C₁ to C₄ lower alkyl group, or hydroxyl group is, for example, obtainedas follows. The pyrimidine derivative (XIIa) where, in general formula(XII), for example, R³ and R⁴ respectively indicate hydrogen atoms, thedotted line indicates the presence of a bond, and the 2-pyrimidinylgroup is bonded at the 4-position or 5-position of the1,2,3,6-tetrahydropyridyl group: ##STR19## is obtained by firstconverting the known compound of 2-chloropyrimidine to2-tri-n-butyltinpyrimidine according to the method described in thedocument of J. Sandosham et al. (Tetrahedron, vol. 50, p. 275, 1994) ora similar method, then converting it to a lithium pyrimidinyl derivativeaccording to the method described in that document or a similar method.Next, this is made to react with a piperidone derivative having theformula (XIII) or (XIV): ##STR20##

wherein, R⁵ indicates a t-butoxycarbonyl group, ethoxycarbonyl group, oracetyl group to obtain a piperidylpyrimidine derivative having theformula (XV): ##STR21##

wherein, R⁵ is as defined above, when the 2-pyrimidinyl group is bondedat the 3-position of the piperidyl group, the hydroxy group is bonded atthe 3-position of the piperidyl group, when the 2-pyrimidinyl group isbonded at the 4-position of the piperidyl group, the hydroxy group isbonded at the 4-position of the piperidyl group.

The obtained piperidylpyrimidine derivative (XV) is reacted with an acidchloride derivative such as thionyl chloride, methanesulfonyl chloride,trifluoromethansulfonyl chloride, phosphorus oxychloride, if necessary,in the presence of a base such as triethylamine or pyridine or reactedwith Burgess reagent (described in E. M. Burgess et al., J. Org. Chem.,vol. 38, p. 26, 1973) to obtain a tetrahydropyrimidine derivative havingthe formula (XV'): ##STR22##

wherein, R⁵ is as defined above, and the 2-pyrimidinyl group in theformula is bonded at the 4-position or 5-position of the1,2,3,6-tetrahydropyridyl group.

Next, if the compound is treated with an acid such as a trifluoroaceticacid, it is possible to obtain a useful synthetic intermediate where inthe formula (XII), R³ and R⁴ respectively indicate a hydrogen atom andthe dotted line indicates the presence of a bond, that is, a2-(1,2,3,6-tetrahydropyridyl) pyrimidine derivative (XIIa).

Further, the synthetic intermediate (XIIa) can be obtained with treatingthe piperidylpyrimidine derivative having the formula (XV) directly withan acid such as trifluoroacetic acid.

The pyrimidine derivative (XIIb) where, in the formula (XII), forexample, R³ and R⁴ respectively indicate a hydrogen atom, the dottedline indicates the absence of a bond, and the 2-pyrimidinyl group isbonded at the 3-position or 4-position of the piperidine group can besynthesized as follows: ##STR23## That is, thetetrahydropyridylpyrimidine derivative having the general formula (XV')is hydrogenated in the presence of a palladium/carbon catalyst to obtainthe piperidylpyrimidine derivative having the formula (XVa): ##STR24##

wherein, R⁵ is the same as defined above, and the bond of the2-pyrimidinyl group and piperidyl group in the formula is at the3-position or 4-position.

The obtained piperidylpyrimidine derivative (XVa) may be treated with anacid such as trifluoroacetic acid to obtain the useful syntheticintermediate 2-piperidylpyrimidine derivative (XIIb).

Further, the 2-piperidylpyrimidine derivative (XIIb) can be obtaineddirectly by catalytic reduction of the2-(1,2,3,6-tetrahydropyridyl)pyrimidine (XIIa).

Further, the pyrimidine derivative having the general formula (XII) canbe synthesized in the following separate method. The compound having theformula (XIIa) in the formula (XII), for example, is obtained by firstconverting 3- or 4-cyanopyridine to 3- or 4-amidinopyridine according tothe method described in the document of H. Fischer et al. (J.Heterocyclic Chem., vol. 17, p. 333, 1980) or a similar method. Next,this is subjected to a condensation dehydration reaction withmalonaldehyde, malonaldehyde bis(dimethylacetal), etc. to obtain thepyrimidylpyridine derivative having the formula (XVI): ##STR25##

wherein, the 2-pyrimidinyl group is bonded at the 3-position or4-position of the pyridine group.

Next, a substituent group R⁶ is introduced to the pyridine ring toconvert this to a compound having the formula (XVII): ##STR26##

wherein, R⁶ indicates a C₁ to C₄ lower alkyl group, benzyl group, ormethoxybenzyl group, X indicates a halogen atom, and the 2-pyrimidinylgroup is bonded at the 3-position or 4-position of the pyridinium group.

Next, this is reduced with sodium borohydride to a compound having theformula (XVIII): ##STR27##

wherein, R⁶ is as defined above, and the 2-pyrimidinyl group is bondedat the 4-position or 5-position of the 1,2,3,6-tetrahydropyridyl group.

Next, this is reacted with ethyl chloroformate, phenyl chloroformate,1-chloroethyl chloroformate, 2-trimethylsilylethyl chloroformate, etc.to obtain the compound having the formula (XIX): ##STR28##

wherein, R⁷ indicates a C₁ to C₄ lower alkyl group, 1-chloroethyl group,phenyl group, or 2-trimethylsilylethyl group and the 2-pyrimidinyl groupis bonded at the 4-position or 5-position of the1,2,3,6-tetrahydropyridyl group.

The compound thus obtained may be decomposed with an alcohol such asmethanol, ethanol, or hydrolyzed with an acid such as hydrochloric acid,acetic acid, sulfuric acid, bromic acid, or with a fluoride such astetrabutylammonium fluoride (TBAF) to obtain the useful syntheticintermediate having the pyrimidinyl derivative (XIIa).

Further, in formula (XII), the formula (XIIb) is obtained byhydrogenating the compound having the formula (XVIII) in the presence ofa palladium/carbon catalyst, if necessary, when adding an acid such ashydrochloric acid to obtain the compound having the formula (XVIIIa):##STR29##

wherein, R⁶ is as defined above, and the bond between the 2-pyrimidinylgroup and piperidyl group is at the 3-position or 4-position. Thecompound thus obtained (XVIIIa) is reacted with ethyl chloroformate,phenyl chloroformate, 1-chloroethyl chloroformate, 2-trimethylsilylethylchloroformate, etc. to obtain the compound having the formula (XIXa):##STR30##

wherein, R⁷ indicates a C₁ to C₄ lower alkyl group, 1-chloroethyl group,phenyl group, or 2-trimethylsilylethyl group, and the 2-pyrimidinylgroup is bonded at the 3-position or 4-position of the piperidyl group.The compound thus obtained may be decomposed with an alcohol such asmethanol, ethanol, or decomposed with a fluoride such astetrabutylammonium fluoride (TBAF) or other fluoride to obtain theuseful synthetic intermediate having the pyrimidine derivative (XIIb).

Further, the piperidylpyrimidine derivative (XIIb) may be obtaineddirectly by catalytic reduction of the1,2,3,6-tetrahydropyridylpyrimidine derivative having the formula(XIIa).

Further, the pyrimidine derivative (XIIc) where, in the formula (XII),for example, R³ indicates an alkyl group, for example, a methyl group,R⁴ indicates a hydrogen atom, the dotted line indicates the presence ofa bond, and the 2-pyrimidinyl group is bonded at the 4-position or5-position of the 1,2,3,6-tetrahydropyridyl group ##STR31##

can be synthesized by causing a condensation and dehydration reactionbetween 3- or 4-amidinopyridine and acetoaldehyde dimethyl acetal toobtain the compound of the formula (XX): ##STR32## then performing thesame procedure as with the compound (XIIa).

Further, the pyrimidine derivative (XIId) where, in formula (XII), forexample, R³ indicates an alkyl group, for example, a methyl group, R⁴indicates a hydrogen atom, the dotted line indicates the absence of abond, and the 2-pyrimidinyl group is bonded at the 3-position or4-position of the piperidyl group ##STR33##

may be synthesized by hydrogenating the above pyrimidine derivative(XIIc) using, if necessary, an acid such as hydrochloric acid.

Further, the pyrimidine derivative (XIIe) where, in the formula (XII),for example, R³ and R⁴ indicate an alkoxy group, for example, a methoxygroup, the dotted line indicates the presence of a bond, and the2-pyrimidinyl group is bonded at the 4-position or 5-position of the1,2,3,6-tetrahydropyridyl group ##STR34## may be synthesized by causinga condensation reaction between 3- or 4-amidinopyridine and malonyldichloride to obtain the compound having the formula (XXI): ##STR35##

then dimethylating the resulting product to convert it to the compound(XXII): ##STR36##

and then following the same procedure as with the compound (XIIa).

Further, the pyrimidine derivative (XIIf) where, in formula (XII), forexample, R³ indicates an alkyl group, for example, a methyl group, R⁴indicates a halogen, for example, a fluoro group, the dotted lineindicates the presence of a bond, and the 2-pyrimidinyl group is bondedat the 4-position or 5-position of the 1,2,3,6-tetrahydropyridyl group##STR37##

may be synthesized by causing a condensation and dehydration reactionwith 2-fluoro-3-oxo-butyroaldehyde dimethyl acetal to obtain a compoundhaving the formula (XXIII): ##STR38##

then following the same procedure as the compound (XIIa).

In the intermediate compounds of the formula (XI), the pyridinederivative may be, for example, produced as follows. It may be obtainedby the method described in the document of W. S. Saari et al. (J. Med.Chem., vol. 27, p. 1182, 1984) or a similar method.

Further, it may be obtained as follows as a separate method. That is,the pyridine derivative (XIa) where, in the formula (XI), for example,Z' indicates a 2-pyridyl group, the dotted line indicates the presenceof a bond, and the 2-pyridyl group is bonded at the 4-position or5-position of the 1,2,3,6-tetrahydropyridyl group ##STR39##

may be synthesized by first converting the known compound 2,4'-dipyridylor 2,3'-dipyridyl to the compound of the formula (XVIIa) in accordancewith the method described in the document of H. Fischer et al. (J.Heterocyclic Chem., vol. 17, p. 333, 1980) or a similar method:##STR40##

wherein, R⁶ indicates a C₁ to C₄ lower alkyl group, benzyl group, ormethoxybenzyl group, X indicates a halogen atom, and the 2-pyridyl groupis bonded at the 3-position or 4-position of the pyridinium group.

Next, this is reduced with sodium borohydride to obtain the compoundhaving the formula (XVIIIb): ##STR41##

wherein, R⁶ is the same as defined above, and the 2-pyridyl group isbonded at the 4-position or 5-position of the 1,2,3,6-tetrahydropyridylgroup.

Next, this is reacted with ethyl chloroformate, phenyl chloroformate,1-chloroethyl chloroformate, or 2-trimethylsilylethyl chloroformate,etc. to obtain the compound having the formula (XIXb): ##STR42##

wherein, R⁷ indicates a C₁ to C₄ lower alkyl group, 1-chloroethyl group,phenyl group, or 2-trimethylsilylethyl group, and the 2-pyridyl group isbonded at the 4-position or 5-position of the 1,2,3,6-tetrahydropyridylgroup. The compound obtained may be decomposed by methanol, ethanol, orother alcohol, hydrolyzed with an acid such as hydrochloric acid, aceticacid, sulfuric acid, hydrobromic acid, or decomposed with a fluoridesuch as tetrabutylammonium fluoride (TBAF) to obtain the usefulsynthetic intermediate having the pyridine derivative (XIa).

Further, the pyridine derivative (XIb) where, in the formula (XI), forexample, Z' indicates a 2-pyridyl group, the dotted line indicates theabsence of a bond, and the 2-pyridyl group is bonded at the 3-positionor 4-position of the piperidyl group ##STR43##

may be synthesized by hydrogenating the compound having the aboveformula (XVIIIb) in the presence of pd/c, while, if necessary adding anacid such as hydrochloric acid, to derive the compound having theformula (XVIIId): ##STR44##

wherein, R⁶ is the same as defined above, and the 2-pyridyl group isbonded at the 3-position or 4-position of the piperidinyl group. Next,this is reacted with ethyl chloroformate, phenyl chloroformate,1-chloroethyl chloroformate, 2-trimethylsilylethyl chloroformate, etc.to obtain the compound having the general formula (XIXd): ##STR45##

wherein, R⁷ indicates a C₁ to C₄ lower alkyl group, 1-chloroethyl group,phenyl group, or 2-trimethylsilylethyl group, and the 2-pyridyl group isbonded at the 3-position or 4-position of the piperidyl group. Theobtained compound (XIXd) may then be decomposed with an alcohol such asmethanol, ethanol, hydrolyzed with an acid such as hydrochloric acid,acetic acid, sulfuric acid, bromic acid, or decomposed with a fluoridesuch as tetrabutylammonium fluoride (TBAF) to obtain the usefulsynthetic intermediate having the pyridyl derivative (XIb).

Further, the piperidylpyridine derivative (XIb) may be obtained directlyby catalytic reduction of the 1,2,3,6-tetrahydropyridine derivativehaving the above formula (XIa).

The compound having the final compound (VI) may be produced bysubstitution condensation of the synthetic intermediate of the formula(XI), for example, the synthetic intermediate pyrimidine derivative(XII) such as illustrated in the above (XIIa to XIIf), or the syntheticintermediate pyridine derivative such as illustrated in the above (XIato XIb) with the synthetic intermediate (Ia), if necessary, using a basesuch as triethylamine, potassium carbonate, or a catalyst such as sodiumiodide.

Synthesis of Final Compound having Formula (VI) by Separate Method

Further, the compound having the final compound (VI) may be synthesizedthrough the compound (XXIV) where, in the formula (VIII), Z' is thefollowing formula (XXV): ##STR46##

wherein Y indicates CH or a nitrogen atom, R³ and R⁴ respectivelyindicate a hydrogen atom, halogen atom, C₁ to C₄ lower alkyl group, orhydroxy group ##STR47##

wherein, X, R, R³, R⁴, Y, X₁, and n are the same as defined above.

Here, the synthetic intermediate having the formula (XXIV) may besynthesized as follows. That is, it is possible to obtain the usefulsynthetic intermediate having the above formula (XXIV) by causing a2,3'-dipyridyl derivative, 2,4'-dipyridyl derivative, or thepyrimidinylpyridine derivative having the above formula (XVI) with thecompound having the above formula (Ia) in the presence of sodium iodide.

It is also possible to produce the compound having the final compound(VI) by reducing the obtained synthetic intermediate (XXIV) with sodiumborohydride.

EXAMPLES

The present invention will now be explained in further detail usingExamples, but the present invention is of course not limited in scope bythese Examples.

Example 1

Synthesis of 4-(4-chlorobutyl)-5-oxo-4,5-dihydro-1 4-benzoxazepin-3-yldiethyl phosphate

30 g of 4-(4-chlorobutyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dioneand 17.4 ml (1.1 equivalents) of diethyl chlorophosphate were dissolvedin 180 ml of tetrahydrofuran, then 112 ml of 1N sodiumbis(trimethylsilyl)amide was dropwise added at -50° C. under a stream ofargon gas. After 1 hour, water was added and extraction performed byethyl acetate. The organic layer was washed with saturated saline, thenwas dried over anhydrous magnesium sulfate. The solvent was distilledoff to obtain 46 g of the above-identified compound (yield 100%). Theproduct was sufficiently pure, but may be purified, if necessary, withsilica gel column chromatography.

Example 2

Synthesis of 3-chloro-4-(4-chlorobutyl)-4,5-dihydro-14-benzoxazepin-5-one

46 g of the compound of Example 1 was dissolved in 250 ml ofacetonitrile, then 44 g (1.3 equivalents) of triphenylphosphine chlorinecomplex was added and the mixture agitated overnight. The reactionsolution was condensed under vacuum and then 500 ml of diisopropyl etherand 500 ml of 10% sodium hydroxide aqueous solution were added to theresidue. The precipitated insolubles were removed by filtration. Thefiltrate was washed 3 times by a 10% aqueous sodium hydroxide solutionand washed with saturated saline. This was dried over anhydrousmagnesium sulfate, then the solvent was distilled off to obtain 30 g ofthe above-referenced compound (yield 96%). The product was sufficientlypure, but may be purified, if necessary, by silica gel columnchromatography.

Example 3

Synthesis of 3-bromo-4-(4-chlorobutyl)4,5-dihydro-1,4-benzoxazepin-5-one

4.6 g of the compound of Example 1 and 6.6 g (2 equivalents) of carbontetrabromide were dissolved in 10 ml of methylene chloride, then 5.2 g(2 equivalents) of triphenylphosphine was added and the mixture agitatedovernight. Water was added and extraction performed by chloroform. Theresultant product was washed by saturated saline, then dried overanhydrous magnesium sulfate. The solvent was distilled off to obtain acrude product which was purified by silica gel column chromatography(hexane:ethyl acetate=4:1) to obtain 1.5 g of the above-referencedcompound (yield 45%).

Example 4

Synthesis of3-chloro-4-(4-chlorobutyl)-4,5-dihydro-1,4-benzoxazepin-5-one (separatemethod of synthesis of same substance as Example 2)

600 mg of the compound of Example 1 was dissolved in 10 ml of methylenechloride, then 470 mg (2 equivalents) of diethyl chlorophosphite wasadded and the mixture agitated for 3 hours. Water was added andextraction performed with chloroform. The resultant product was washedtwo times with a 10% aqueous sodium hydroxide solution and then washedwith saturated saline. This was dried over anhydrous magnesium sulfate,then the solvent was distilled off to obtain 350 mg of theabove-referenced compound (yield 82%). The product was sufficientlypure, but may be purified, if necessary, by silica gel columnchromatography.

Example 5

Synthesis of3-chloro-4,5-dihydro-4-(4-(4-(2-pyridyl)pyridinio-1-yl)butyl)-1,4-benzoxazepin-5-onechloride

200 mg of the compound of Example 2 was dissolved in 2 ml of acetone,then 21 mg (2 equivalents) of sodium iodide and 120 mg (1.1 equivalents)of 2,4'-dipyridine were added and the mixture heated and refluxed for 30hours. The mixture was then allowed to cool, then the precipitatedcrystals were obtained by filtration. Recrystallization was performedwith a mixed solvent of methanol, acetone, and ether to obtain 298 mg ofthe above-referenced compound (yield 96%).

Example 6

Synthesis of3-chloro-4,5-dihydro-4-(4-(4-(2-pyrimidinyl)pyridinio-1-yl)butyl)-1,4-benzoxazepin-5-onechloride

500 mg of the compound of Example 2 was dissolved in 10 ml of acetone,then 390 mg (1.5 equivalents) of sodium iodide and 330 mg (1.1equivalents) of 4-(2-pyrimidyl)pyridine were added and the mixtureheated and refluxed for 48 hours. The mixture was then allowed to cool,then the precipitated crystals were obtained by filtration.Recrystallization was performed with acetone to obtain 860 mg of theabove-referenced compound (yield 100%).

Example 7

Synthesis of 4-(2-pyridinyl)-1,2,3,6-tetrahydropyridine (1)

Step 1) Synthesis ofN-t-butoxycarbonyl-4-hydroxy-4-(2-pyrimidinyl)piperidine

4.74 g of 2-tri-n-butyltinpyrimidine was dissolved in 30 ml oftetrahydrofuran (hereinafter referred to as THF), then 12 ml (1.5equivalents) of 1.6N n-butyllithium/hexane solution was added dropwisein a stream of nitrogen gas at -78° C. After 30 minutes, 30 ml of a THFsolution of 3.06 g (1.2 equivalents) of N-t-butoxycarbonyl-4-piperidonewas dropwise added, then the reaction temperature was gradually raisedto room temperature. Ice water was added to the reaction solution thenextraction was performed with ethyl acetate. The resultant product waswashed with water and saturated saline, then dried over anhydrousmagnesium sulfate. The solvent was distilled off to obtain a crudeproduct which was then purified by silica gel column chromatography(hexane:ethyl acetate=2:1) to obtain 1.10 g of the above-referencedcompound (yield 26%).

Step 2) Synthesis ofN-t-butoxycarbonyl-4-(2-pyrimidinyl)-1,2,3,6-tetrahydropyridine

2.11 g of the compound of Step 1 of Example 7 was dissolved in 30 ml ofpyridine, then 1.0 ml (1.4 equivalents) of phosphorous oxychloride wasadded under ice cooling and the resultant product was agitated for 15hours. The pyridine was distilled off under reduced pressure, then a 10%aqueous sodium hydroxide solution was added and extraction performedwith methylene chloride. The organic layer was washed with saturatedsaline, then was dried over anhydrous magnesium sulfate. The solvent wasdistilled off to obtain a crude product which was then purified bysilica gel column chromatography (hexane:ethyl acetate=2:1) to obtain1.01 g of the above-referenced compound (yield 51%).

Step 3) Synthesis of 4-(2-pyrimidinyl)-1,2,3-6-tetrahydropyridine

500 mg of the compound of Step 2 of Example 7 was dissolved in 10 ml ofmethylene chloride, then 3.5 ml of trifluoroacetic acid (hereinafterreferred to as TFA) was added and the resultant product agitated at roomtemperature for 30 minutes. This was concentrated, then a 10% aqueoussodium hydroxide solution was added and extraction performed withchloroform. The organic layer was washed with saturated saline, thendried over anhydrous magnesium sulfate. The chloroform solution wasconcentrated to obtain 260 mg of the above-referenced compound (yield87%).

Example 8

Synthesis of 4-(2-pyrimidinyl)piperidine

Step 1) Synthesis of N-t-butoxycarbonyl-4-(2-pyrimidinyl)piperidine

490 mg of the compound of Step 2 of Example 7 was dissolved in 10 ml ofethanol, then 100 mg of 10% palladium carbon was added and the resultantproduct agitated under a stream of hydrogen gas for 2 days. The catalystwas filtered off and the ethanol distilled off. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain160 mg of the above-referenced compound (yield 33%).

Step 2) Synthesis of 4-(2-pyrimidinyl)piperidine

1.5 g of the compound of Step 1 of Example 8 was dissolved in 30 ml ofmethylene chloride, then 10 ml of TFA was added and the resultantproduct agitated at room temperature for 30 minutes. The same procedurewas then followed as in Step 3 of Example 6 to obtain 750 mg of theabove-referenced compound (yield 82%).

Example 9

Synthesis of 4-(2-pyrimidinyl)-1,2,3,6-tetrahydropyridine (2)

Step 1) Synthesis of 4-(2-pyrimidinyl)pyridine 35 mg (0.04 equivalent)of sodium was dissolved in 5 ml of methanol, then 4.0 g of4-cyanopyridine was added. After 30 minutes, 2.0 g (1 equivalent) ofammonium chloride was added and the resultant product agitated for 24hours. The solution was concentrated to about half, then 5 ml of acetonewas added. The precipitated crystal was obtained by filtration to obtain4-amidinopyridine chlorate. This was dissolved in 2.2 ml (5 equivalents)of water, then 5.0 ml (1.2 equivalents) of 1,1,3,3-tetramethoxypropaneand 1.4-dioxane (2 ml) were added and the resultant product agitated at130° C. for 1 hour to dry it to a solid. This was allowed to cool, thena 10% aqueous sodium hydroxide solution was added and extractionperformed by ethyl acetate. The resultant product was washed with waterand saturated saline, then dried over anhydrous magnesium sulfate. Thesolvent was distilled off to obtain 2.58 g of the above-referencedcompound (yield 65%).

Step 2) Synthesis of1-benzyl-4-(2-pyrimidinyl)-1,2,3,6-tetrahydropyridine

652 mg of the compound of Step 1 of Example 9 was dissolved in 10 ml ofacetonitrile, then 0.96 ml (2 equivalents) of benzylchloride was addedand the resultant product heated and refluxed for 20 hours. This wasconcentrated, then the residue was recrystallized with a mixed solventof acetonitrile and ether to obtain pyridinium. The resultant productwas dissolved in ethanol (5 ml) and 307 mg (2 equivalents) of sodiumborohydride was added. After 30 minutes, water was added and extractionperformed with ethyl acetate. This was washed with water and saturatedsaline, then dried over anhydrous magnesium sulfate. The solvent wasdistilled off to obtain a product which was then purified by silica gelcolumn chromatography (methylene chloride:methanol 30:1) to obtain 968mg of the above-referenced compound (yield 95%).

Step 3) Synthesis of 4-(2-pyrimidinyl)-1,2,3-6-tetrahydropyridine

710 mg of the compound of step 2 of Example 9 was dissolved in 10 ml ofdichloroethane, then 0.31 ml (1 equivalent) of 1-chloroethylchlorocarbonate was added and the resultant product heated and refluxedfor 1 hour. This was concentrated once, then methanol was added againand the resultant product heated and refluxed for 1 hour. This wasconcentrated, then recrystallized with a mixed solvent of methanol andether to obtain 471 mg of a chloride of the above-referenced compound(yield 84%).

Example 10

Synthesis of 4-(4-methylpyrimidin-2-yl)-1,2,3,6-tetrahydropyridine

Step 1) Synthesis of1-benzyl-4-(4-methylpyrimidin-2-yl)-1,2,3,6-tetrahydropyridine

274 mg of 4-(4-methylpyrimidin-2-yl)pyridine was dissolved in 5 ml ofacetonitrile, then 0.40 ml (2 equivalents) of benzylchloride was addedand the resultant product heated and refluxed for 10 hours. This wasconcentrated, then the residue was recrystallized with a mixed solventof acetonitrile and ether to obtain a pyridinium salt. This wasdissolved in ethanol (3 ml) and 129 mg (2 equivalents) of sodiumborohydride added. After 30 minutes, water was added and extractionperformed by ethyl acetate. The same procedure was then followed as instep 2 of Example 9 for the reaction, treatment, and purification toobtain 409 mg of the above-referenced compound (yield 94%).

Step 2) Synthesis of4-(4-methylpyrimidin-2-yl)-1,2,3,6-tetrahydropyridine

300 mg of the compound of Step 1 of Example 10 was dissolved in 5 ml ofdichloroethane, then 0.14 ml (1 equivalent) of 1-chloroethylchlorocarbonate was added and the resultant product heated and refluxedfor 1 hour. This was concentrated once, then methanol was again addedand the resultant product heated and refluxed for 1 hour. The resultantproduct was concentrated, then recrystallized with a mixed solvent ofmethanol and ether to obtain 213 mg of a chloride of theabove-referenced compound (yield 88%).

Example 11

Synthesis of 5-(2-pyrimidinyl)-1,2,3,6-tetrahydropyridine

Step 1) Synthesis ofN-t-butoxycarbonyl-3-hydroxy-3-(2-pyrimidinyl)piperidine

5.0 g of 2-tri-n-butyltinpyrimidine was dissolved in 60 ml of THF, then12 ml (1.5 equivalents) of 1.7N n-butyllithium/hexane solution wasdropwise added under a stream of nitrogen gas at -78° C. After 1 hour,30 ml of a THF solution of 3.24 g (1.2 equivalents) ofN-t-butoxycarbonyl-3-piperidone was dropwise added, then the reactiontemperature was gradually raised to room temperature. Aqueous saturatedammonium chloride solution was added to this reaction solution andextraction performed with ethyl acetate. The resultant product waswashed with water and saturated saline, then dried over anhydrousmagnesium sulfate. The solvent was distilled off to obtain a productwhich was then purified by silica gel column chromatography (methylenechloride:methanol=20:1) to obtain 1.10 g of the above-referencedcompound (yield 29%).

Step 2) Synthesis ofN-t-butoxycarbonyl-5-(2-pyrimidinyl)-1,2,3,6-tetrahydropyridine

1.56 g of the compound of Step 1 of Example 11 was dissolved in 15 ml ofpyridine, then 0.8 ml (1.5 equivalents) of phosphorus oxychloride wasadded under ice cooling and the resultant product agitated for 16 hours.The same procedure was followed as in Step 2 of Example 7 for thereaction, treatment, and purification to obtain 285 mg of theabove-referenced compound (yield 20%).

Step 3) Synthesis of 5-(2-pyrimidinyl)-1,2,3,6-tetrahydropyridine

260 mg of the compound of Step 2 of Example 11 was dissolved in 5 ml ofmethylene chloride, then 2 ml of TFA was added and the resultant productagitated at room temperature for 30 minutes. The same procedure wasfollowed as in Step 3 of Example 7 for the reaction, treatment, andpurification to obtain 146 mg of the above-referenced compound (yield91%).

Example 12

Synthesis of 3-(2-pyrimidinyl)piperidine

Step 1) Synthesis of N-t-butoxycarbonyl-3-(2-pyrimidinyl)piperidine

490 mg of the compound of Step 2 of Example 11 was dissolved in 10 ml ofethanol, then 40 mg of 10% palladium carbon was added and the resultantproduct agitated under a stream of hydrogen gas for 15 hours. The sameprocedure was followed as in Step 1 of Example 8 for the reaction,treatment, and purification to obtain 100 mg of the above-referencedcompound (yield 50%).

Step 2) Synthesis of 3-(2-pyrimidinyl)piperidine

140 mg of the compound of Step 1 of Example 12 was dissolved in 5 ml ofmethylene chloride, then 2 ml of TFA was added and the resultant productagitated at room temperature for 30 minutes. The same procedure wasfollowed as in Step 3 of Example 11 for the reaction, treatment, andpurification to obtain 70 mg of the above-referenced compound (yield81%).

Example 13

Synthesis of3-chloro-4,5-dihydro-4-(3-(4-(2-pyrimidinyl)piperadin-1-yl)propyl)-1,4-benzoxazepin-5-one

200 mg of the3-chloro-4-(3-chloropropyl)-4,5-dihydro-1,4-benzoxazepin-5-onesynthesized by the method of Example 15 described in InternationalPublication WO96/24594 was dissolved in 6 ml of dimethylformamide, then180 mg (1.5 equivalents) of 1-(2-pyrimidinyl)piperadine, 220 mg (2equivalents) of sodium iodide, and 0.21 ml (2 equivalents) oftriethylamine were added and the resultant product agitated at 80° C.for 15 hours. This was allowed to cool, then water was added andextraction performed twice with ethyl acetate. The entire organic layerwas washed with an aqueous saturated sodium bicarbonate solution andsaturated saline, then dried over anhydrous magnesium sulfate. Thesolvent was distilled off to obtain a crude product which was thenpurified by silica gel column chromatography (methylenechloride:methanol=30:1) to obtain 140 mg of the above-referencedcompound (yield 48%). Note that the chloride was obtained by making achloride by an ordinary method, then recrystallizing from a mixedsolvent of methanol and ether.

Example 14

Synthesis of3-chloro-4,5-dihydro-4-(4-(4-(2-pyridyl)piperadin-1-yl)butyl)-1,4-benzoxazepin-5-one

287 mg of the compound of Example 2 was dissolved in 9 ml ofdimethylformamide, then 0.24 ml (1.6 equivalents) of1-(2-pyridyl)piperadine, 300 mg (2 equivalents) of sodium iodide, and0.29 ml (2 equivalents) of triethylamine were added and the resultantmixture was agitated at 80° C. for 14 hours. The resultant mixture wastreated and purified in the same way as Example 13 to obtain 167 mg ofthe above-referenced compound (yield 41%). Note that the fumarate wasobtained by making a fumarate by an ordinary method, thenrecrystallizing from a mixed solvent of ethanol and diisopropyl ether.

Example 15

Synthesis of3-chloro-4,5-dihydro-4-(4-(4-(4-quinazolyl)piperadin-1-yl)butyl)-1,4-benzoxazepin-5-one

429 mg (1.5 equivalents) of the compound of Example 2 was dissolved in10 ml of dimethylformamide, then 214 mg of 1-(4-quinazolyl)piperadine,300 mg (2 equivalents) of sodium iodide, and 0.28 ml (2 equivalents) oftriethylamine were added and the resultant mixture agitated at 80° C.for 15 hours. This was treated and purified in the same way as Example13 to obtain 380 mg of the above-referenced compound (yield 83%). Notethat the chloride was obtained by making a chloride by an ordinarymethod, then recrystallizing by acetone.

Example 16

Synthesis of3,8-dichloro-4,5-dihydro-4-(4-(4-(2-pyridyl)piperadin-1-yl)butyl)-1,4-benzoxazepin-5-one

169 mg of the4-(4-chlorobutyl)-3,8-dichloro-4,5-dihydro-1,4-benzoxazepin-5-onesynthesized by the method of Example 17 described in InternationalPublication WO96/24594 was dissolved in 3 ml of dimethylformamide, then129 mg (1.5 equivalents) of 1-(2-pyridyl)piperadine, 158 mg (2equivalents) of sodium iodide, and 106 mg (2 equivalents) oftriethylamine were added and the resultant mixture agitated at 80° C.for 6 hours. This was treated and refined in the same way as Example 13to obtain 219 mg of the above-referenced compound (yield 93%). Note thatthe dichloride was obtained by making a dichloride by an ordinarymethod, then recrystallizing from a mixed solvent of methanol,chloroform, and ether.

Example 17

Synthesis of3-chloro-4,5-dihydro-7-methyl-4-(4-(4-(2-pyrimidinyl)piperadin-1-yl)butyl)-1,4-benzoxazepin-5-one

129 mg of the3-chloro-4-(4-chlorobutyl)-4,5-dihydro-7-methyl-1,4-benzoxazepin-5-onesynthesized by the method of Example 19 described in InternationalPublication WO96/24594 was dissolved in 2 ml of dimethylformamide, then106 mg (1.5 equivalents) of 1-(2-pyrimidinyl)piperadine, 129 mg (2equivalents) of sodium iodide, and 87 mg (2 equivalents) oftriethylamine were added and the resultant mixture agitated at 90° C.for 7 hours. This was then treated and purified in the same way asExample 13 to obtain 152 mg of the above-referenced compound (yield83%). Note that the dichloride was obtained by making a dichloride by anordinary method, then recrystallizing from ether.

Example 18

Synthesis of3-chloro-4,5-dihydro-4-(4-(4-(2-pyrimidinyl)-1,2,3,6-tetrahydropyridin-1-yl)butyl)-1,4-benzoxazepin-5-one

128 mg of the compound of Example 7 was dissolved in 10 ml of DMF, then335 mg (1.5 equivalents) of the compound of Example 2, 238 mg (2equivalents) of sodium iodide, and 0.22 ml (2 equivalents) oftriethylamine were added and the resultant mixture agitated at 80° C.for 14 hours. This was treated and purified in the same way as Example13 to obtain 86 mg of the above-referenced compound (yield 26%). Notethat the chloride was obtained by making a chloride by an ordinarymethod, then recrystallizing from a mixed solvent of methanol andacetone.

Example 19

Synthesis of3-chloro-4,5-dihydro-4-(4-(4-(2-pyrimidinyl)piperidin-1-yl)butyl)-1,4-benzoxazepin-5-one

46 mg of the compound of Example 8 was dissolved in 5 ml of DMF, then120 mg (1.5 equivalents) of the compound of Example 2, 84 mg (2equivalents) of sodium iodide, and 0.08 ml (2 equivalents) oftriethylamine were added and the resultant mixture agitated at 80° C.for 12 hours. This was treated and purified in the same way as Example13 to obtain 98 mg of the above-referenced compound (yield 84%). Notethat the chloride was obtained by making a chloride by an ordinarymethod, then recrystallizing from a mixed solvent of methanol andacetone.

Example 20

Synthesis of3-chloro-4,5-dihydro-4-(4-(5-(2-pyrimidinyl)-1,2,3,6-tetrahydropyridin-1-yl)butyl)-1,4-benzoxazepin-5-one

70 mg of the compound of Example 11 was dissolved in 8 ml of DMF, then150 mg (1.2 equivalents) of the compound of Example 2, 156 mg (2.4equivalents) of sodium iodide, and 0.15 ml (2.4 equivalents) oftriethylamine were added and the resultant mixture agitated at 80° C.for 13 hours. This was treated and purified in the same way as Example13 to obtain 36 mg of the above-referenced compound (yield 20%). Notethat the fumarate was obtained by making a fumarate by an ordinarymethod, then recrystallizing from acetone.

Example 21

Synthesis of3,8-dichloro-4,5-dihydro-4-(4-(4-(2-pyrimidinyl)-1,2,3,6-tetrahydropyridin-1-yl)butyl)-1,4-benzoxazepin-5-one

50 mg of the compound of Example 9 was dissolved in 5 ml of DMF, then 66mg (1.5 equivalents) of the starting compound used in Example 16, 62 mg(2 equivalents) of sodium iodide, and 42 mg (2 equivalents) oftriethylamine were added and the resultant mixture agitated at 90° C.for 6 hours. This was treated and purified in the same way as Example 13to obtain 39 mg of the above-referenced compound (yield 43%). Note thatthe fumarate was obtained by making a fumarate by an ordinary method,then recrystallizing from a mixed solvent of methanol and ether.

Example 22

Synthesis of3,8-dichloro-4,5-dihydro-4-(4-(4-(2-pyrimidinyl)piperidin-1-yl)butyl)-1,4-benzoxazepin-5-one

70 mg of the compound of Example 8 was dissolved in 5 ml of DMF, then206 mg (1.5 equivalents) of the starting compound used in Example 16,145 mg (2.3 equivalents) of sodium iodide, and 97 mg (2.3 equivalents)of triethylamine were added and the resultant mixture agitated at 90° C.for 6 hours. This was treated and purified in the same way as Example 13to obtain 177 mg of the above-referenced compound (yield 92%). Note thatthe fumarate was obtained by making a fumarate by an ordinary method,then recrystallizing from ether and making an amorphous powder.

Example 23

Synthesis of3-chloro-4,5-dihydro-8-methoxy-4-(4-(4-(2-pyrimidinyl)-1,2,3,6-tetrahydropyridin-1-yl)butyl)-1,4-benzoxazepin-5-one

70 mg of the compound of Example 9 was dissolved in 6 ml of DMF, then150 mg (1.1 equivalents) of3-chloro-4-(4-chlorobutyl)-4,5-dihydro-8-methoxy-1,4-benzoxazepin-5-onesynthesized by the method of Example 18 described in InternationalPublication WO 96/24594, 142 mg (2.2 equivalents) of sodium iodide, and0.13 ml (2.2 equivalents) of triethylamine were added and the resultantmixture agitated at 80° C. for 14 hours. This was treated and purifiedin the same way as Example 13 to obtain 60 mg of the above-referencedcompound (yield 32%). Note that the fumarate was obtained by making afumarate by an ordinary method, then recrystallizing from ether.

Example 24

Synthesis of3-chloro-4,5-dihydro-8-methoxy-4-(4-(4-(2-pyrimidinyl)piperidin-1-yl)butyl)-1,4-benzoxazepin-5-one

70 mg of the compound of Example 8 was dissolved in 6 ml of DMF, then150 mg (1.1 equivalents) of the3-chloro-4-(4-chlorobutyl)-4,5-dihydro-8-methoxy-1,4-benzoxazepin-5-onesynthesized by the method of Example 18 described in InternationalPublication WO 96/24594, 142 mg (2.2 equivalents) of sodium iodide, and0.13 ml (2.2 equivalents) of triethylamine were added and the resultantmixture agitated at 80° C. for 15 hours. This was treated and purifiedin the same way as Example 13 to obtain 177 mg of the above-referencedcompound (yield 92%). Note that the fumarate was obtained by making afumarate by an ordinary method, then recrystallizing from acetone andether.

Example 25

Synthesis of3,8-dichloro-4,5-dihydro-4-(4-(4-(2-pyridyl)-1,2,3,6-tetrahydropyridin-1-yl)butyl)-1,4-benzoxazepin-5-one

200 mg of the starting compound used in Example 16 was dissolved in 5 mlof DMF, then 120 mg (1.2 equivalents) of4-(2-pyridyl)-1,2,3,6-tetrahydropyridine, 187 mg (2 equivalents) ofsodium iodide, and 0.17 ml (2 equivalents) of triethylamine were addedand the resultant mixture agitated at 90° C. for 18 hours. This wastreated and purified in the same way as Example 13 to obtain 117 mg ofthe above-referenced compound (yield 43%). Note that the fumarate wasobtained by making a fumarate by an ordinary method, thenrecrystallizing from a mixed solution of methanol and ether.

Example 26

Synthesis of3,8-dichloro-4,5-dihydro-4-(4-(4-(2-pyridyl)piperidin-1-yl)butyl)-1,4-benzoxazepin-5-one

200 mg of the starting compound used in Example 16 was dissolved in 5 mlof DMF, then 149 mg (1.2 equivalents) of 4-(2-pyridyl)piperidinechlorate, 187 mg (2 equivalents) of sodium iodide, and 0.30 ml (3.5equivalents) of triethylamine were added and the resultant mixtureagitated at 90° C. for 20 hours. This was treated and purified in thesame way as Example 13 to obtain 158 mg of the above-referenced compound(yield 59%). Note that the fumarate was obtained by making a fumarate byan ordinary method, then recrystallizing from a mixed solvent ofmethanol and ether.

Example 27

Synthesis of3-chloro-4,5-dihydro-4-(3-(4-(2-pyridyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-1,4-benzoxazepin-5-one

200 mg of the starting compound used in Example 13 was dissolved in 5 mlof DMF, then 141 mg (1.2 equivalents) of4-(2-pyridyl)-1,2,3,6-tetrahydropyridine, 220 mg (2 equivalents) ofsodium iodide, and 0.21 ml (2 equivalents) of triethylamine were addedand the resultant mixture agitated at 90° C. for 18 hours. This wastreated and purified in the same way as Example 13 to obtain 150 mg ofthe above-referenced compound (yield 52%). Note that the fumarate wasobtained by making a fumarate by an ordinary method, thenrecrystallizing from a mixed solvent of methanol and ether.

Example 28

Synthesis of3-chloro-4,5-dihydro-4-(3-(4-(2-pyridyl)piperidin-1-yl)-propyl)-1,4-benzoxazepin-5-one

200 mg of the starting compound used in Example 13 was dissolved in 5 mlof DMF, then 175 mg (1.2 equivalents) of 4-(2-pyridyl)piperidinechlorate, 220 mg (2 equivalents) of sodium iodide, and 0.36 ml (3.5equivalents) of triethylamine were added and the resultant mixtureagitated at 90° C. for 20 hours. This was treated and purified in thesame way as Example 13 to obtain 160 mg of the above-referenced compound(yield 55%). Note that the fumarate was obtained by making a fumarate byan ordinary method, then making an amorphous powder.

Example 29

Synthesis of3-chloro-4,5-dihydro-4-(5-(4-(2-pyridyl)-1,2,3,6-tetrahydropyridin-1-yl)pentyl)-1,4-benzoxazepin-5-one

250 mg of the compound of the3-chloro-4-(5-bromopentyl)-4,5-dihydro-1,4-benzoxazepine-5-onesynthesized by the method described in Example 20 of InternationalPublication WO96/24594 was dissolved in 5 ml of acetonitrile, then 139mg (1.2 equivalents) of 4-(2-pyridyl)-1,2,3,6-tetrahydropyridine and0.20 ml (2 equivalents) of triethylamine were added and the resultantmixture heated and refluxed for 8 hours. This was treated and refined inthe same way as Example 13 to obtain 110 mg of the above-referencedcompound (yield 37%). Note that the fumarate was obtained by making afumarate by an ordinary method, then recrystallizing from a mixedsolvent of methanol and ether.

Example 30

Synthesis of3-chloro-4,5-dihydro-4-(4-(4-((4-methyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridin-1-yl)butyl)-1,4-benzoxazepin-5-one

200 mg of the compound of Example 2 was dissolved in 5 ml of DMF, then178 mg (1.2 equivalents) of a chlorate of4-(4-methylpyrimidin-2-yl)-1,2,3,6-tetrahydropyridine synthesized by themethod described in Example 28 of International Publication WO96/24594,210 mg (2 equivalents) of sodium iodide, and 0.34 ml (3.5 equivalents)of triethylamine were added and the resultant mixture agitated at 90° C.for 20 hours. This was treated and purified in the same way as Example13 to obtain 154 mg of the above-referenced compound (yield 54%). Notethat the fumarate was obtained by making a fumarate by an ordinarymethod, then recrystallizing from a mixed solvent of methanol and ether.

Example 31

Synthesis of3-chloro-4,5-dihydro-4-(4-(4-(2-pyridyl)piperidin-1-yl)butyl)-1,4-benzoxazepin-5-one

550 mg of the compound of Example 2 was dissolved in 10 ml of DMF, then210 mg (1.2 equivalents) of 4-(2-pyridyl)piperidine, 390 mg (2equivalents) of sodium iodide, and 0.36 ml (2 equivalents) oftriethylamine were added and the resultant mixture agitated at 90° C.for 17 hours. This was treated and purified in the same way as Example13 to obtain 450 mg of the above-referenced compound (yield 85%). Notethat the fumarate was obtained by making a fumarate by an ordinarymethod, then recrystallizing from acetone.

Example 32

Synthesis of3-chloro-4,5-dihydro-4-(4-(4-(2-pyridyl)-1,2,3,6-tetrahydropyridin-1-yl)butyl)-1,4-benzoxazepin-5-one

487 mg of the compound of Example 2 was dissolved in 10 ml of DMF, then180 mg (1.2 equivalents) of a 4-(2-pyridyl)-1,2,3,6-tetrahydropyridine,336 mg (2 equivalents) of sodium iodide, and 0.31 ml (2 equivalents) oftriethylamine were added and the resultant mixture agitated at 90° C.for 20 hours. This was treated and refined in the same way as Example 13to obtain 290 mg of the above-referenced compound (yield 63%). Note thatthe acid addition salt was made a dichlorate by an ordinary method, thenrecrystallizing the crude product obtained from a mixed solvent ofisopropyl alcohol and water (13:1). This was repeatedly recrystallizedfrom the same mixed solvent to obtain a dichloride of theabove-referenced compound (yield 66% from free amines).

Example 33

Synthesis of3-chloro-4,5-dihydro-4-(4-(5-(2-pyridyl)-1,2,3,6-tetrahydropyridin-1-yl)butyl)-1,4-benzoxazepin-5-one

102 mg of the compound of Example 2 was dissolved in 2 ml of DMF, then52 mg (0.9 equivalent) of 5-(2-pyridyl)-1,2,3,6-tetrahydropyridine, 107mg (2 equivalents) of sodium iodide, and 66 mg (2 equivalents) oftriethylamine were added and the resultant mixture agitated at 90° C.for 20 hours. This was treated and purified in the same way as Example13 to obtain 65 mg of the above-referenced compound (yield 49%). Notethat the fumarate was obtained by making a fumarate by an ordinarymethod, then making an amorphous powder.

Example 34

Synthesis of3-chloro-4,5-dihydro-4-(4-(4-(2-pyrimidinyl)-1,2,3,6-tetrahydropyridin-1-yl)butyl)-1,4-benzoxazepin-5-one(Synthesis of the same compound of Example 18 by another method)

560 mg of the the3-chloro-4,5-dihydro-4-(4-(4-(2-pyrimidinyl)pyridinio-1-yl)butyl)-1,4-benzoxazepin-5-onechloride described in Example 24 of International Publication WO96/24594was dissolved in 15 ml of ethanol, then 98 mg (2 equivalents) of sodiumborohydride was added under ice cooling and the resultant mixtureagitated at room temperature for 10 minutes. Water was added andextraction performed with ethyl acetate. The organic layer was washedwith water and saturated saline, then was dried over anhydrous magnesiumsulfate. The solvent was distilled off to obtain a crude product whichwas then purified by silica gel column chromatography (methylenechloride:methanol=30:1) to obtain 462 mg of the above-referencedcompound (yield 89%).

Example 35

Synthesis of3-chloro-4,5-dihydro-4-(4-(4-(2-pyridyl)-1,2,3,6-tetrahydropyridin-1-yl)butyl)-1,4-benzoxazepin-5-one(synthesis of identical substance as Example 32 by different method)

800 mg of the compound of Example 5 was dissolved in 20 ml of ethanol,140 mg (2 equivalents) of sodium borohydride was added under icecooling, then the result was agitated at room temperature for 10minutes. Water was added and extraction was performed with ethylacetate. The organic layer was washed with water and saturated saline,then was dried with anhydrous magnesium sulfate. The solvent wasdistilled off and the resultant crude product was refined with silicagel column chromatography (methylene chloride:methanol=30:1), to obtainthe above-referenced compound in an amount of 600 mg (yield of 81%).

    TABLE I       - Example Formula and Property IR (cm.sup.-1) NMR (δppm)     Remarks       1      ##STR48##      3007, 1703  1653, 1606  1456, 1393  1338, 1278  1152  (CHCl.sub.3)     7.85(1H, d, J=8Hz), 7.42(1H, t, J=8Hz),  7.21(1H, t, J=8Hz), 7.02(1H, d,       J=8Hz),  6.86(1H, d, J=2Hz), 4.09-4.15(4H, m),  3.82-3.87(2H, m),     3.57-3.61(2H, m),  1.85-1.89(4H, m), 1.28(6H, t, J=7Hz)  (CHCl.sub.3)     404  (FAB-MS)     2      ##STR49##      2956, 1704  1644, 1605  1574, 1538  1479, 1236  (NaCl) 7.86-7.89(1H,     m), 7.43-7.47(1H, m),  7.22-7.26(1H, m), 7.02(1H, d, J=8Hz),  6.73(1H,     s), 3.94(2H, t, J=6Hz),  3.57-3.60(2H, m), 1.86-1.89(4H, m)  (CDCl.sub.3)       286  (FAB-MS)     3      ##STR50##      2958, 1704  1646, 1606  1566, 1533  1477  (NaCl) 7.88(1H, dd, J=8Hz,     2Hz),  7.45(1H, dd, J=8Hz, 2Hz),  7.24(1H, t, J=8Hz), 7.01(1H, d,     J=8Hz),  6.76(1H, s), 3.91-3.97(2H, m),  3.56-3.60(2H, m), 1.85-1.89(4H,       m)  (CDCl.sub.3) 330, 332  (FAB-MS)     4      ##STR51##      2956, 1704  1644, 1604  1574, 1538  1479, 1236  (NaCl) 7.86∝7.89(      1H, m), 7.43-7.47(1H, m),  7.22-7.26(1H, m), 7.02(1H, d, J=8Hz),     6.73(1H, s), 3.94(2H, t, J=6Hz),  3.57-3.60(2H, m), 1.86-1.89(4H, m)     (CDCl.sub.3) 286  (FAB-MS)         m.p.         (Recrystallization  MS/Elementary       Example Chemical Structure Solvent) IR (cm.sup.-1) NMR (δppm)     Analysis       5      ##STR52##       3445 3008  1642 1603  1561 1475  1456 1342  1177  (KBr) 9.21(2H, d,     J=7Hz), 8.87(1H, d, J=4Hz),  8.81(2H, d, J=7Hz), 8.44(1H, d, J=8Hz),     8.11(1H, d, t, J=2Hz, 8Hz),  7.77(1H, dd, J=2Hz, 8Hz),  7.66(1H, dd,     J=4Hz, 8Hz),  7.58(1H, dt, J=2Hz, 8Hz), 7.33(1H, t, J=8Hz),  7.14 (1H,     d, J=8Hz), 7.10(1H, s),  4.71(2H, t, - #   J=7Hz), 3.87 (2H, t, J=7Hz),       2.01-2.12(2H, m), 1.65-1.71(2H, m)  (DMSO-d.sub.6)     6      ##STR53##       3450 2365  1652 1553  1454 1414  1338 1201  1105  (KBr) 9.49 (2H, d,     J=7Hz), 8.96-8.98(4H, m),  7.82-7.84(1H, m), 7.45-7.47(2H, m),  7.23-7.28      (1H, m), 7.02 (1H, d, J=7Hz),  6.74(1H, s), 5.19(2H, t, J=8Hz),     4.03(2H, t, J=7Hz), 2.20-2.25(2H, m),  1.93-1.98(2H, m) (CDCl.sub.3)                                                                          7     Step 1      ##STR54##       8.74(2H, d, J=5Hz), 7.22(1H, t, J=5Hz),  4.02-4.15(2H, m), 3.11-3.32(4H      , m),  2.16-2.25(2H, m), 1.49 (9H, s)  (CDCl.sub.3) FAB-Mass  280     (M+H).sup.+     7  Step 2      ##STR55##       3018 1682  1556 1421  1368 1241  1168  (CHCl.sub.3) 8.69(2H, d,     J=5Hz), 7.15-7.21(1H, m),  7.10(1H, t, J=5Hz), 4.17-4.22(2H, m),     3.64(2H, t, J=6Hz), 2.70-2.78(2H, m),  1.49(9H, s)  (CDCl.sub.3) FAB-MAS        262 (M+H).sup.+     7  Step 3      ##STR56##       3021 2984  1571 1557  1423 1210  1206  (CHCl.sub.3) 8.68(2H, d,     J=5Hz), 7.27-7.29(2H, m),  3.12(2H, t, J=6Hz), 2.62-2.66(2H, m),  7.09     (1H, t, J=5Hz), 3.62-3.64(2H, m),  (CDCl.sub.3) FAB-Mass  162 (M+H).sup.+     8  Step 1      ##STR57##       3024 1682  1563 1506  1426 1367  1248  (CHCl.sub.3) 8.68(2H, d,     J=5Hz), 7.13(1H, t, J=5Hz),  4.15-4.28(2H, m), 3.00-3.06(1H, m),     2.85-2.91(2H, m), 1.98-2.02(2H, m),  1.75-1.87(2H, m), 1.47(9H, s)     (CDCl.sub.3) FAB-Mass  264 (M+H).sup.+     8  Step 2      ##STR58##       3023 3017  1574 1563  1427 1228  1206  (CHCl.sub.3) 8.68(2H, d,     J=5Hz), 7.12(1H, t, J=5Hz),  3.20-3.24(2H, m), 2.99-3.06(1H, m),     2.75-2.82(2H, m), 2.00-2.04(2H, m),  1.76-1.86(2H, m)  (CDCl.sub.3)     FAB-Mass  164 (M+H).sup.+     9  Step 1      ##STR59##       3027 1734  1668 1596  1547 1385  1218  (KBr) 8.87 (2H, d, J=5Hz),     8.78(2H, d, J=5Hz),  8.29 (2H, d, J=5Hz), 7.30(1H, t, J=5Hz)  (CDCl.sub.3      )     9  Step 2      ##STR60##       2910 2809  1654 1568  1533 1494  1424 1374  (KBr) 8.67(2H, d, J=5Hz),     7.38-7.39(2H, m),  7.33(2H, t, J=7Hz), 7.26-7.27(1H, m),  7.20-7.22(1H,     m), 7.07(1H,t, J=5Hz),  3.67(2H, s), 3.23-3.27(2H, m),  2.82-2.88(4H, m)        (CDCl.sub.3)     9  Step 3      ##STR61##       3374 2956  2793 2612  1659 1608  1568 1556  1426 1390  (KBr) 9.27(2H,     brs), 8.81(2H, d, J=5Hz),  7.39(1H, t, J=5Hz), 7.15-7.18(1H, m),     3.81-3.87(2H, m), 3.30-3.36(2H, m),  2.81-2.85(2H, m)  (DMSO-d.sub.6)                                                                           10        Step 1      ##STR62##       3019 2400  1652 1520  1418 1213  1046  (CHCl.sub.3) 8.50(1H, d,     J=5Hz), 7.33-7.38(2H, m),  7.30-7.32(2H, m), 7.23-7.27(1H, m),  7.17(1H,       t, J=3Hz), 6.92(1H, d, J=5Hz),  3.66 (2H, s), 3.25(2H, d, J=3Hz),     2.74(4H, s), 2.48(3H, s)  (CDCl.sub.3)     10  Step 2      ##STR63##       2956 2841  1657 1578  1554 1441  1393 1367  1251  (KBr) 9.08-9.35(2H,     brs), 8.65(1H, d, J=5Hz),  7.28(1H, t, J=5Hz), 7.13(1H, s),  3.83(2H,     brs), 3.30-3.31(2H, m),  2.79-2.80(2H, m), 2.47(3H, s)  (DMSO-d.sub.6)     11  Step 1      ##STR64##       3022 1683  1574 1420  1394 1367  1276  (CHCl.sub.3) 8.74(2H, d,     J=5Hz), 7.23(1H, t, J=5Hz),  4.07-4.10(1H, m), 3.81-3.92(1H, m),     3.35-3.45(1H, m), 2.94-3.00(1H, m),  1.81-1.84(1H, m), 1.70-1.73(1H, m),        2.18-2.22(1H, m), 2.00-2.05(1H, m),  1.45(9H, s) (CDCl.sub.3)     FAB-Mass  280 (M+H).sup.+     11  Step 2      ##STR65##       1684 1570  1556 1421  1367 1280  (CHCl.sub.3) 8.67(2H, d, J=5Hz),     7.37-7.39(1H, m),  7.10(1H, t, J=5Hz), 4.44-4.48(2H, m),  3.58(2H, t,     J=6Hz), 2.39-2.43(2H, m),  1.50(9H, s)  (CDCl.sub.3) FAB-Mass  262     (M+H).sup.+     11  Step 3      ##STR66##       3036 2952  1653 1627  1569 1558  1424 1229  (CHCl.sub.3) 8.66(2H, d,     J=5Hz), 7.36-7.38(IH, m),  7.09(1H, t, J=5Hz), 3.95(2H, s),  3.08(2H, t,       J=6Hz), 2.41-2.44(2H, m)  (CDCl.sub.3) FAB-Mass  162 (M+H).sup.+                                                                        12     Step 1      ##STR67##       2848 1734  1681 1573  1422 1368  1269  (CHCl.sub.3) 8.67(2H, d,     J=5Hz), 7.14(1H, t, J=5Hz),  4.28-4.35(1H, m), 4.10-4.18(1H, m),     2.98-3.16(2H, m), 2.75-2.85(1H, m),  2.14-2.20(1H, m), 1.75-1.84(2H, m),        1.55-1.60(1H, m), 1.46(9H, s)  (CDCl.sub.3) FAB-Mass  264 (M+H).sup.+     12  Step 2      ##STR68##       2929 2253  1466 1148  (CHCl.sub.3) 8.68 (2H, d, J=5Hz), 7.14 (1H, t,     J=5Hz),  3.00-3.14(2H, m), 2.74-2.81(1H, m),  2.33-2.35(2H, m), 2.16-2.21      (1H, m),  2.05-2.09(1H, m), 1.54-1.59(2H, m)  (CDCl.sub.3) FAB-Mass     164 (M+H).sup.+     13      ##STR69##      178-180°  C. (2)  (EtOH--Et.sub.2 O) 3698 2934  2572 2458  1662     1605  1586 1478  1456 1362  1201  (2) (KBr) 10.1(1H, brs), 8.44 (2H, d,     J=5Hz),  7.78-7.81(1H, m), 7.61(1H, t, J=7Hz),  7.33-7.37(1H, m), 7.18     (1H, s),  7.16(1H, d, J=7Hz), 6.76(1H, t, J=5Hz), 4.69-4.73(2H, m),     3.85-3.89(2H, m),  3.05-3.60(8H, m), - #   2.11-2.20(2H, m),  (2)     (DMSO-d.sub.6) MAB-Mass  400 (M+H).sup.+     14      ##STR70##      158-161°  C. (1)  (EtOH-iPr.sub.2 O) 3430 2949  1704 1657  1594     1480  1455 1438  1247 1158  984  (1) (KBr) 8.08-8.11(1H, m), 7.77-7.81(1H      , m),  7.48-7.63(2H, m), 7.33(1H, t, J=7Hz),  7.17(1H, d, J=7Hz),     7.16(1H, s),  6.80(1H, d, J=9Hz), 6.61 (4H, s),  6.60-6.65(1H, m),     3.85(2H, t, J=7Hz),  - #   3.47(4H, t, J=5Hz), 2.44-2.50(4H, m),  2.40     (2H, t, J=7Hz), 1.62-1.72(2H, m),  1.48-1.58(2H, m) (1) (DMSO-d.sub.6)     Elementary  Analysis  C.sub.26 H.sub.29 N.sub.4 O.sub.6 Cl      C  H   N        Calcd: .sup. 59.03 5.53 10.59  Found: 58.70 5.54      10.50                                                        15      ##STR71##      219-222°  C. (2)  (acetone) 2448 1654  1608 1570  1546 1474     1450 1353  1100  (2) (KBr) 11.33(1H, br, s), 8.92(1H, s),  8.21(1H, d,     J=8Hz), 8.04(1H, t, J=8Hz),  7.96(1H, d, J=8Hz), 7.78-7.80(1H, m),     7.73(1H, t, J=8Hz), 7.58-7.62(1H, m),  7.34(1H, t, J=7Hz), 7.16(2H, t,     J=7Hz), - #   4.74(2H, d, J=11Hz), 3.99(2H, br, s),  3.86(2H, t, J=7Hz),       3.64(2H, d, J=11Hz),  3.17-3.28(4H, m), 1.70-1.81(4H, m)  (2) (DMSO-d.s      ub.0) FAB-Mass  464(M+H).sup.+     1 As fumarate, indicated as (1).     2 As chloride, indicated as (2).       16      ##STR72##      133-135°  C. (3)  (MeOH--CHCl.sub.3 --  Et.sub.2 O) 3450 2872     1664 1621  1568 1414  1300 1095  986  (3) (KBr) 8.17(1H, d, J=5Hz),     7.82(1H, d, J=9Hz),  7.46(1H, t, J=9Hz), 7.22(1H, d, J=8Hz),  7.05(1H,     s), 6.69(1H, s),  6.58-6.64(2H, m), 3.92(2H, t, J=7Hz),  3.54(4H,     J=5Hz), 2.54(4H, t, J=5Hz), - #   2.43(2H, t, J=7Hz), 1.70-1.79(2H, m),       1.55-1.64(2H, m) (CDCl.sub.3) FAB-Mass  447(M+H).sup.+     17      ##STR73##      100-101°  C. (3)  (Et.sub.2 O) 3434 2918  2593 1700  1622  1586       1552 1490  227  954  (3) (KBr) 8.29(2H, d, J=5Hz), 7.66(1H, s),     7.23(1H, d, J=8Hz), 6.89(1H, d, J=8Hz),  6.70(1H, s), 6.46(1H, t,     J=5Hz),  3.92(2H, t, J=7Hz), 3.82(4H, t, J=5Hz),  2.49(4H, t, J=5Hz),     2.42(2H, t, J=7Hz), - #   2.33(3H, s), 1.72-1.81(2H, m),  1.55-1.69(2H,     m) (CDCl.sub.3) FAB-Mass  428(M+H).sup.+     18      ##STR74##      147-151°  C. (2)  (MeOH-acetone) 3394 2930  1661 1605  1453 1422        1379 1200  (2) (KBr) 10.15(1H, brs), 8.82(2H, d, J=5Hz),  7.79(1H, d,       J=8Hz), 7.60(1H, t, J=8Hz),  7.33-7.43(2H, m), 7.13-7.14(3H, m),     4.09-4.13(1H, m), 3.85-3.88(3H, m),  3.65-3.70(1H, m), 3.24-3.27(3H, m),        2.85-2.99(2H, m), 1.10-1.85(4H, m)  - #   (2) (DMSO-d.sub.6) FAB-Mass        411(M+H).sup.+     19      ##STR75##      110-113°  C. (2)  (acetone) 3051 2946  1646 1604  1564 1478     1456 1426  (2) (KBr) 10.15(1H, brs), 8.78(2H, d, J=5Hz),  7.80(1H, d,     J=8Hz), 7.58-7.62(1H, m),  7.33-7.40(2H, m), 7.14-7.17(2H, m),  3.84-3.87      (2H, m), 3.54-3.57(2H, m),  3.03-3.15(5H, m), 2.05-2.20(4H, m),     1.66-1.85(4H, m)  (2) (DMSO-d.sub.6) - #   FAB-Mass  413(M+H).sup.+     1 As chloride, indicated as (2).     2 As dichloride, indicated as (3).       20      ##STR76##      124-126°  C. (1)  (acetone) 2926 2576  1699 1649  1560 1478     1422 1378  (1) (KBr) 8.73(2H, d, J=5Hz), 7.78(1H, d, J=8Hz),  7.58(1H,     t, J=7Hz), 7.29-7.34(2H, m),  7.23(1H, s), 7.11-7.15(2H, m),  6.60(4H,     s), 3.84-3.89(2H, m),  3.42-3.51(2H, m), 2.59-2.62(4H, m),  2.31-2.40(2H,       m), 1.61-1.70(4H, m)  (1)(DMSO-d.sub.6) - #   FAB-Mass  411(M+H).sup.+     21      ##STR77##      181-183°  C. (1)  (MeOH--Et.sub.2 O) 3014 2539  1716 1658  1598     1556  1416 1298  (1) (KBr) 8.67(2H, d, J=5Hz), 7.82(1H, d, J=7Hz),     7.26-7.27(1H, m), 7.22(1H, dd, J=2Hz, 7Hz),  7.05(1H, d, J=2Hz),     7.01(1H, t, J=5Hz),  6.70(1H, s), 3.92(2H, t, J=7Hz),  3.25-3.29(2H, m),       2.69-2.80(4H, m),  2.55(2H, t, J=7Hz), 1.66-1.75 (4H, m) - #     (CDCl.sub.3) FAB-Mass  445(M+H).sup.+     22      ##STR78##      amorphous (1) 2926 1661  1619 1562  1429  (1) (KBr) 8.74(2H, d, J=5Hz),       7.80(1H, d, J=9Hz),  7.41(1H, d, J=9Hz),7.33(1H, t, J=5Hz),  7.29(1H,     s), 7.11(1H,s),  6.59(4H, s), 3.82-3.89(2H, m),  3.15-3.21(2H, m),     2.91-2.99(1H, m),  2.67-2.72(2H, m), 2.50-2.59(2H, m),  1.90-2.08(4H,     m), 1.61-1.72(4H, m)  (1) (DMSO-d.sub.6) - #   FAB-Mass  447(M+H).sup.+     23      ##STR79##      110-112°  C. (1)  (Et.sub.2 O) 292 1657  1647 1616  1560 1540     1422 1328  (1) (KBr) 8.76(2H, d, J=5Hz), 7.72(1H, d, J=9Hz),  7.32(1H,     t, J=5Hz), 7.14-7.16(1H, m),  7.07(1H, s), 6.89(1H, d, J=2Hz),  6.69(1H,       d, J=2Hz), 6.62(4H, s),  3.81-3.83(5H, m), 3.33-3.37(2H, m),  2.78-2.85      (2H, m), 2.63-2.67(4H, m)  - #   1.60-1.68(4H, m) (1) (DMSO-d.sub.6)     FAB-Mass  441(M+H).sup.+     24      ##STR80##      178-181°  C. (1)  (acetone-Et.sub.2 O) 2926 1665  1609 1561     1428 1264  (1) (KBr) 8.76(2H, d, J=3Hz). 7.73(1H, d, J=9Hz),  7.38(1H,     t, J=3Hz), 7.09(1H, d, J=4Hz),  6.90-6.92(1H, m), 6.70(1H, s),  6.63(4H,       s), 3.80-3.85(5H, m),  3.52-3.57(2H, m), 3.05-3.18(5H, m),  2.16-2.20(2      H, m), 1.95-2.05(2H, m),  1.63-1.72(4H, m), - #   (1) (DMSO-d.sub.6)     FAB-Mass  443(M+H).sup.+     25      ##STR81##      167-170°  C. (1)  (MeOH--Et.sub.2 O) 3432 2946  1660 1600  1567     1470  1414 1331  1201  (1) (KBr) 8.51(1H, d, J=4Hz), 7.80(1H, d, J=8Hz),        7.73(1H, t, J=8Hz), 7.51(1H, d, J=8Hz),  7.40(1H, d, J=9Hz), 7.30(1H,       s),  7.21(1H, t, J=6Hz), 7.12(1H, s),  6.65(1H, s), 6.62(4H, s),     3.85(2H, t, J=7Hz), 3.19-3.25(2H, m),  - #       2.70-2.77(2H, m), 2.52-2.63(4H, m),  1.64-1.73(2H, m), 1.53-1.64(2H,     m)  (1) (DMSO-d.sub.6) FAB-Mass  444(M+H).sup.+     26      ##STR82##      161-164°  C. (1)  (MeOH--Et.sub.2 O) 3427 2947  1662 1599  1469     1475  1436 1289  1243  (1) (KBr) 8.48(1H, d, J=4Hz), 7.80(1H, d, J=8Hz),        7.69(1H, t, J=4Hz), 7.41(1H, dd, J=2Hz, 8Hz),  7.30(1H, d, J=2Hz),     7.25(1H, d, J=8Hz),  7.18(1H, t, J=4Hz), 7.13(1H, s),  6.59(4H, s),     3.85(2H, t, J=7Hz),  3.06(2H, d, J=10Hz), - #   2.68-2.72(1H, m),     2.45-2.55(2H, m), 2.14-2.25(2H, m),  1.76-1.86(4H, m), 1.62-1.68(2H, m),        1.53-1.61(2H, m) (1) (DMSO-d.sub.6) FAB-Mass  446(M+H).sup.+     27      ##STR83##      148-151°  C. (1)  (MeOH-Et.sub.2 O) 3420 2920  1662 1604  1454     1372  1332 1278  (1) (KBr) 8.51(1H, d, J=5Hz), 7.79(1H, d, J=8Hz),     7.73(1H, t, J=8Hz), 7.57(1H, t, J=8Hz),  7.50(1H, d, J=8Hz), 7.32(1H, t,       J=8Hz),  7.21(1H, t, J=4Hz), 7.14(1H, d, J=8Hz),  7.09(1H, s),     6.67(1H, s),  6.62(4H, s), 3.88(2H, t, J=7Hz),  - #   2.70(2H, t,     J=6Hz), 2.51-2.59(6H, m),  1.87-1.93(2H, m) (1) (DMSO-d.sub.6) FAB-Mass       396(M+H).sup.+     1 As fumarate, indicated as (1).       28      ##STR84##      amorphous (1) 3440 2947  2656 2351  1651 1455  1336 1201  (1) (KBr)     8.48(1H, d, J=4Hz), 7.79(1H, d, J=7Hz),  7.69(1H, t, J=8Hz), 7.58(1H, t,       J=7Hz),  7.33(1H, t, J=8Hz), 7.25(1H, d, J=8Hz),  7.14-7.20(2H, m),     7.10(1H, s),  6.61(4H, s), 3.87(2H, t, J=6Hz),  3.08(2H, d, J=11Hz),     2.67-2.70(1H, m),  2.23(2H, t, J=10Hz), 1.79-1.88(6H, m) - #     (1)     (DMSO-d.sub.6) FAB-Mass  398(M+H).sup.+     29      ##STR85##      123-126°  C. (1)  (MeOH--Et.sub.2 O) 3441 2942  1644 1604  1454     1377  1329 1247  (1) (KBr) 8.51(1H, d, J=4Hz), 7.78(1H, d, J=8Hz),     7.73(1H, t, J=7Hz), 7.57(1H, t, J=7Hz),  7.49(1H, d, J=8Hz), 7.32(1H, t,       J=8Hz),  7.22(1H, t, J=4Hz), 7.13(1H, d, J=8Hz),  7.11(1H, s),     6.64(1H, s),  6.60(4H, s), 3.83(2H, t, J=7Hz),  - #   3.19-3.22(2H, m),     2.70(2H, t, J=6Hz),  2.59-2.63(2H, m), 2.49-2.58(2H, m),  1.64-1.75(2H,     m), 1.55-1.63(2H, m),  1.35-1.45(2H, m) (1) (DMSO-d.sub.6) FAB-Mass     424(M+H).sup.+     30      ##STR86##      121-124°  C. (1) 3424 2940  2582 1655  1578 1454  1372 1330     1249  (1) (KBr) 8.63(1H, d, J=5Hz), 7.78-7.80(1H, m),  7.58-7.62(1H, m),       7.34(1H, t, J=8Hz),  7.25(1H, d, J=5Hz), 7.15-7.17(1H, m),  7.09(1H,     s),6.63(4H, s),  3.80-3.88(2H, m), 2.95-3.40(2H, m),  2.73-2.80(2H, m),     2.48-2.57(4H, m),  2.46(3H, s), 1.65-1.73 - #       (4H, m)  (1) (DMSO-d.sub.6) FAB-Mass  425(M+H).sup.+     31      ##STR87##      158-161°  C. (2)  (acetone) 3428 2946  2672 1648  1540 1454     1378 1330  1241  (2) (KBr) 9.71(1H, br), 8.55-8.59(1H, m), 7.89-7.91(1H,       m), 7.79(1H, d, J=8Hz),  7.60(1H, t, J=8Hz), 7.31-7.40(3H, m),     7.14-7.18(2H, m), 3.84-3.87(2H, m),  3.55-3.58(2H, m), 2.95-3.18(5H, m),        2.04-2.15(4H, m), 1.68-1.89(4H, m)  (2) (DMSO- - #   d.sub.6)     FAB-Mass  412(M+H).sup.+     1 As fumarate, indicated as (1).     2 As chloride, indicated as (2).       32      ##STR88##      145-147°  C. (2)  (MeOH-acetone)  3416 2928  2695 1652  1604     1560  1455 1381  1340 1198  (2) (KBr) 10.74(1H, br),8.61-8.63(1H, m),     7.95-7.97(1H, m) 7.79(1H, dd, J=2, 8Hz),  7.70-7.72(1H, m) 7.60(1H, t,     J=8Hz),  7.42-7.44(1H, m) 7.34(1H, t, J=8Hz),  7.14-7.17(2H, m),     6.74-6.76(1H, m),  - #       4.03-4.08(1H, m), 3.84-3.87(3H, m),  3.64-3.67(1H, m), 3.21-3.25(3H,     m),  2.91-2.93(2H, m), 1.84-1.86(2H, m),  1.70-1.76(2H, m), (2) (DMSO-d.s      ub.6) FAB-Mass  410(M+H).sup.+     33      ##STR89##      amorphous (1) 3439 2933  1700 1683  1630 1570  1433 1291  (1) (KBr)     8.50 (1H, d, J=5Hz) 7.79(1H, d, J=7Hz),  7.74(1H, t, J=7Hz), 7.58-7.62(2H      , m),  7.33(1H, t, J=7Hz), 7.25(1H, t, J=5Hz),  7.12-7.15(2H, m),     6.72(1H, s),  6.60(4H, s), 3.90--3.94(2H, m),  3.64-3.68(2H, m),     2.73-2.80(4H, m),  2.39-2.40(2H, m), 1.66-1.71(4H, m)  - #   (1)     (DMSO-d.sub.6) FAB-Mass  410(M+H).sup.+     1 As fumarate, indicated as (1).     2 As chloride, indicated as (2).

INDUSTRIAL APPLICABILITY

As explained above, according to the present invention, it is possibleto industrially advantageously produce a4-substituted-3-halogeno-1,4-benzoxazepine derivative, an importantcompound which may be used as a pharmaceutical for psychoneuroticdisorders such as anxiety neurosis, phobias, obsessive-compulsivedisorders, schizophrenia, post-cardiac trauma stress disorders,depression disorders, psychosomatic disorders, disorders such as eatingdisorders, menopausal disorders, infantile autism and also emesis ordisorders involving the cerebral circulatory system accompanyingcerebral infarction and cerebral hemorrhaging or as a synthesizingstarting material or intermediate of pharmaceuticals etc., without therisk of occurrence of hydrochloric acid gas or a sudden rise intemperature or bumping in a neutralization reaction for treatment ordecomposition of excessive acid chloride as in the process of theconventional method and further at a high yield without the accompanyingdifficulty of separation of the starting compound and the desiredcompound.

What is claimed is:
 1. A process for producing4-substituted-3-halogeno-1,4-benzoxazepin derivative or the salt thereofcomprising:deprotonizing a benzoxazepine derivative having the formula(II): ##STR90## wherein R indicates a hydrogen atom, halogen atom, C₁ toC₄ lower alkyl group, C₁ to C₄ lower alkoxy group, or hydroxy group, andA indicates a C₂ to C₅ halogenoalkyl group or a group having the formula(III): ##STR91## wherein n is an integer of 2 to 5, the dotted lineindicates the presence or absence of a bond, W indicates a carbon atom,methine, methylene, or nitrogen atom, where when W is a nitrogen atom, Zbonds with W and the dotted line indicates the absence of a bond, and Zindicates an aromatic hydrocarbon group which may be substituted or aheterocyclic group which may be substituted, with a base; and then,reacting the deprotonized product with a phosphate halide to produce anintermediate having the formula (IV): ##STR92## wherein, R and A are asdefined above, and R₁ and R₂ independently indicate, a C₁ to C₂ loweralkyl group or phenyl group or R₁ and R₂ together indicate an ethylenegroup (--CH₂ CH₂ --); and then, reacting the resultant intermediate (IV)with a reagent selected from (i) a complex of a tri(C₁ to C₄)alkylphosphine, triarylphosphine, or phenyldi(C₁ to C₄) alkylphosphinewith chlorine or bromine, (ii) a tri(C₁ to C₄) alkylphosphine,triarylphosphine, or phenyldi(C₁ to C₄) alkylphosphine and a chlorinegas or liquid bromine, (iii) a tri(C₁ to C₄) alkylphosphine,triarylphosphine, or phenyldi(C₁ to C₄) alkylphosphine andtetrachloromethane or tetrabromomethane, or (iv) a halogenated phosphiteester to produce a 4-substituted-3-halogeno-1,4-benzoxazepine derivativehaving the formula (I) ##STR93## wherein, R and A are as defined aboveand X indicates a chlorine atom or a bromine atom, or its salt.
 2. Aprocess as claimed in claim 1, wherein R in the formulae (I), (II) and(IV) indicates a hydrogen atom or halogen atom, X indicates a chlorineatom, A indicates a C₂ -C₅ halogenoalkyl group or a group having theformula (XXVI) or (XXVII): ##STR94## wherein n is an integer of 2 to 5,Ar is a phenyl group, 2-pyridyl group or 2-pyrimidinyl group.
 3. Aprocess as claimed in claim 1, wherein the compound having the formula(II) is reacted with 1 to 1.2 equivalents of the base at a temperatureof -78° C. to 0° C. in the presence of an organic solvent.
 4. A processas claimed in claim 1, wherein the amount of the phosphate halide is 1to 1.2 equivalents based upon the compound having the formula (II).
 5. Aprocess as claimed in claim 1, wherein the intermediate having theformula (IV) is reacted with 1 to 2 equivalents, based upon theintermediate (IV), of the reagent (i), (ii), (iii), or (iv) at a roomtemperature to 80° C. in the presence of an organic solvent.